Cocaine addiction is a major problem for which there is currently no solution. This proposal is focused on developing an anti-cocaine vaccine designed to suppress the pharmacokinetics of cocaine after administration, sufficient to prevent cocaine from reaching its receptors in the brain. Our strategy is based on our almost 2 decades of experience with adenovirus (Ad) gene transfer vectors in experimental animals and humans, and the recognition that these vectors act as potent adjuvants that activate the immune system by infecting antigen presenting cells. We hypothesize that linking cocaine analogs to the proteins on the virion capsid (hexon, fiber, penton) will elicit high level, high affinity cocaine-specific antibodies sufficient to treat cocaine addiction. These capsid modifications will allow the vector to function similarly to a protein immunogen with the added benefit of exploiting the natural adjuvant effect of the Ad. The humoral adaptive immunity induced by Ad is directed against the capsid proteins, including 720 hexons and 96 combined penton bases and fibers, abundant targets for conjugating cocaine. The Ad-cocaine vaccine could be used as a single administration, or more likely, by readministration in a prime-boost fashion to boost the immunity against the drug epitopes. Based on the preliminary data demonstrating the feasibility of evoking high titer anti- cocaine antibodies in mice with human serotype 5 or non-human primate serotype C7 Ad with a cocaine analog coupled to the Ad capsid, we propose a focused, rapid-development, multi-component national program with the deliverable at the end of yr 2 to be an adenovirus-based cocaine vaccine ready to move into human clinical trials. To accomplish this, we have formulated the following specific aims: Aim 1 - To develop a panel of Ad5- and AdC7-based anti-cocaine vaccines that elicit high titer, high affinity anti-cocaine antibodies and that will modify the pharmacokinetics of cocaine in murine models;Aim 2 - Using rat models to assess the ability of the best candidate vaccines from aim 1 to evoke anti-cocaine antibodies, suppress the pharmacokinetics of cocaine following administration, and to prevent cocaine-induced behavioral phenotypes;and Aim 3 - Choosing the best candidate vaccine with the optimal performance from aim 2, assess the ability of the vaccine to modify the pharmacokinetics of cocaine and prevent cocaine-related behavioral phenotypes in non-human primates addicted to cocaine. In aims 2 and 3, studies with GMP-produced vaccines will permit parallel collection of toxicology data to support a future FDA Investigational New Drug application for initial clinical studies. PUBLIC HEALTH RELEVANCE: This is an accelerated, focused pre-clinical program to develop a novel adenovirus (Ad)-based vaccine against cocaine addiction. An Ad-based anti-cocaine vaccine exploits the inherent immunogenicity of Ad to elicit high levels of cocaine neutralizing antibodies sufficient to eliminate cocaine from the circulation prior to reaching its receptors in the brain. We will chemically conjugate cocaine analogs to the surface of the Ad surface for display to the immune system, determine serum anti-cocaine antibody titers in immunized rodents and evaluate pharmacokinetics and behavioral phenotypes in rodent and non-human primate models of cocaine challenge. The deliverable is, at the end of the 2 yr grant, an adenovirus-based cocaine vaccine ready to move into human clinical trials